Efficacy and Safety of Carisbamate (YKP509) as Adjunctive Therapy for Lennox-Gastaut Syndrome-Associated Seizures in Pediatric and Adult Patients

Trial ID: 2023-506616-41-00
Protocol: YKP509C003
Sponsor: Sk Life Science Inc.

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Diseases & Conditions

Lennox-Gastaut syndrome

Objectives

The primary objective of this study is to evaluate the **efficacy** of carisbamate (YKP509) as an adjunctive treatment in reducing the number of drop seizures, including tonic, atonic, and tonic-clonic seizures, compared with placebo in pediatric and adult subjects aged 4-55 years diagnosed with Lennox-Gastaut syndrome (LGS). This is clinically relevant as LGS is a severe form of epilepsy characterized by multiple types of seizures, and effective management of drop seizures can significantly improve patient outcomes and quality of life.

Secondary objectives include:

Evaluating the efficacy of carisbamate in reducing the total number of seizures compared with placebo in the LGS population.
Assessing the safety and tolerability of carisbamate in subjects with LGS.
Evaluating the steady-state pharmacokinetics of carisbamate in subjects with Lennox-Gastaut syndrome.

Participants

The clinical trial involves a total of **150 participants** diagnosed with **Lennox-Gastaut syndrome (LGS)**, a severe form of epilepsy. The study population includes both male and female subjects, ranging in age from 4 to 55 years. Participants were selected based on a documented history of LGS, characterized by multiple seizure types, including atonic or tonic seizures, and a history of developmental delay. The trial includes individuals who have experienced at least eight drop seizures during a four-week baseline period. Participants are required to have been on a stable regimen of 1 to 4 concomitant anti-seizure medications for at least four weeks prior to the study. Additionally, any dietary therapy or central nervous system stimulator settings must remain stable throughout the trial. The study population is considered vulnerable, and all participants or their caregivers must be able to maintain accurate seizure diaries and comply with study requirements. The trial does not exclude based on gender, and both male and female subjects are included. Participants must have a history of COVID-19 vaccination, and those of childbearing potential must adhere to an acceptable method of birth control during the study period.

Plans and Procedures

The clinical trial is designed to evaluate the **efficacy** and safety of **carisbamate** as an adjunctive treatment for seizures associated with **Lennox-Gastaut syndrome** (LGS) in both pediatric and adult populations. This study is structured as a randomized, double-blind, placebo-controlled trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments, thereby minimizing bias. The trial is expected to span from April 2022 to June 2028, with participant involvement lasting up to 76 weeks, depending on individual response and adherence to the protocol.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as a documented history of LGS and a stable regimen of anti-seizure medications. Following successful screening, participants will be randomized to receive either carisbamate or a placebo in the form of an oral suspension. The primary endpoint is the percentage change from baseline in the frequency of countable drop seizures during the double-blind treatment period. Secondary endpoints include the percentage of subjects achieving a significant reduction in seizure frequency and the Subject/Caregiver Global Impression of Change score.

Study visits will include regular follow-up assessments to monitor safety, efficacy, and compliance with the study protocol. These visits will involve clinical evaluations, seizure diary reviews, and any necessary adjustments to the treatment regimen. The end-of-study visit will conclude the participant's involvement, with a comprehensive assessment of the treatment's impact on seizure frequency and overall condition. Participants may be withdrawn from the study early if they experience significant adverse effects, fail to comply with the study protocol, or if the investigator deems it in their best interest. The trial's design and procedures are meticulously crafted to ensure the collection of robust data while prioritizing participant safety and well-being.

Treatment

The clinical trial involves the administration of **Carisbamate**, an experimental medication, formulated as an oral suspension. Carisbamate is chemically derived and is provided by SK Life Science, Inc. The active substance in this formulation is carisbamate, with a European substance number of SUB130483. The maximum daily dose of carisbamate is 600 mg, with a total maximum dose of 319,200 mg over a treatment period of up to 76 days. The medication is administered orally, and the dosing schedule is designed to ensure consistent therapeutic levels. Participant compliance with the dosing regimen is monitored throughout the trial to ensure adherence to the protocol.

In addition to the experimental treatment, a **placebo** is used as a comparator in this double-blind, placebo-controlled study. The placebo is designed to mimic the carisbamate oral suspension in appearance and administration route, ensuring that neither the participants nor the investigators can distinguish between the active treatment and the placebo. The placebo is administered orally, following the same dosing schedule as the carisbamate, to maintain the integrity of the study's blinding process. Compliance with the placebo administration is also monitored to ensure the reliability of the trial results.

Efficacy

The efficacy of Carisbamate (YKP509) as an adjunctive treatment for seizures associated with **Lennox-Gastaut Syndrome** (LGS) will be assessed through a randomized, double-blind, placebo-controlled clinical trial. The primary endpoint for evaluating efficacy is the percentage change from baseline in the total frequency of countable drop seizures (tonic, atonic, tonic-clonic) with potential to fall, measured as an average per 28 days during the double-blind treatment period. Secondary endpoints include the percentage of subjects achieving at least a 50% reduction from baseline in the frequency of countable drop seizures, the percentage change from baseline in the frequency of all types of seizures, and the Subject/Caregiver Global Impression of Change (S/CGI-C) score at the last visit.

Data collection will occur throughout the double-blind treatment period, with specific timepoints for assessment not explicitly detailed. The trial will involve both pediatric and adult subjects aged 4-55 years, who have a documented history of LGS and meet the inclusion criteria. The study will ensure that subjects maintain a stable regimen of concomitant anti-seizure medications and any dietary or CNS stimulator therapies. The efficacy assessments will be conducted using validated scales and patient-reported outcomes, ensuring a comprehensive evaluation of the treatment's impact on seizure frequency and overall condition.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Subject must have a documented history of Lennox-Gastaut syndrome by: a. Evidence of more than one type of seizure, of which at least one should be an atonic or tonic seizure b. History of an electroencephalogram (EEG) reporting diagnostic criteria for LGS (abnormal background activity accompanied by slow, spike and wave pattern <3.0 Hz) c. History of developmental delay 2. Male or female subjects 3. Subjects must be age 4-55 years at the time of consent/assent 4. Must have been <11 years old at the onset of LGS 5. Subjects must have experienced at least 8 drop seizures with potential to fall (tonic, atonic, tonic-clonic) during the 4-week Baseline period preceding randomization (minumim of 4 drop seizures in the first two weeks and 4 in the last two weeks). Drop seizures are defined as a countable seizure involving the entire body, trunk, or head that led or could have led to a fall, injury, slumping in a chair, or hitting the subject's head on a surface. All drop seizure types must be countable (either as isolated seizures or as countable isolated seizures in a cluster).
Subjects must have been receiving 1 to 4 concomitant anti-seizure medications (ASMs) at a stable dose for at least 4 weeks before Visit 1 7. If not taking Epidiolex, subjects may take other approved cannabidiol or over the counter cannabidiol products. If taking cannabidiol other than Epidiolex, consult Medical Monitor to determine if it counts as a concomitant ASM. 8. Dietary therapy and any CNS stimulator settings must be stable for 4 weeks prior to baseline and maintain stable regimen throughout the study. The dietary therapy and CNS stimulators are not counted as an ASM. 9. Parents or caregivers must be able to keep accurate seizure diaries 10. Subject is either not of childbearing potential, defined as premenarchal, postmenopausal for at least 1 year or surgically sterile (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy), if of childbearing potential, must comply with an acceptable method of birth control during the study, for at least 4 weeks prior to study entry and for 2 weeks after dose of study drug. 11. Subject and/or caregiver/legal representative must be willing and able to give informed assent/consent for participation in the study 12. Subject and their caregiver must be willing and able (in the investigator's opinion) to comply with all study requirements 13. History of COVID-19 vaccination is permitted.

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Exclusion Criteria

Etiology of subject's seizures is a progressive neurologic disease. Subjects with tuberous sclerosis will not be excluded from study participation, unless there is a progressive brain tumor2. Evidence of clinically significant disease (e.g., cardiac, respiratory, gastrointestinal, renal disease, hepatic disease) that in the opinion of the investigator(s) could affect the subject's safety or study conduct 3. Subjects who were on adrenocorticotropic hormone (ACTH) therapy in the 6 months prior to baseline 4. Subject on dietary therapy for less than 4 weeks prior to screening visit (Visit 1) or suffers from frequent stooling 5. Current use of felbamate with less than 12 months of continuous exposure 6. Subjects who took vigabatrin in the past must have discontinued it at least 5 months before Visit 1. Subjects taking vigabatrin should have documentation showing no evidence of a vigabatrin-associated visual field abnormality. 7. Subject who had a history of hypoxia which needed emergency resuscitation within 12 months prior to baseline 8. Status epilepticus within 12 weeks prior to Visit 1 9. Any clinically significant illness (including COVID-19) in the 4 weeks prior to Visit 1, as evaluated by the Investigator 10. Subject has clinically significant abnormal laboratory values, in the investigator's opinion, at Visit 1 or time of randomization (Visit 2)
Subject has a history of any serious drug-induced hypersensitivity, e.g., toxic epidermal necrolysis, or Drug Reaction with Eosinophilia and Systemic Symptoms [DRESS]) or any drug-related rash requiring hospitalization 12. Vagus Nerve Stimulation (VNS), Deep Brain Stimulation (DBS), Responsive Neurostimulator System (RNS) or other neurostimulation for epilepsy device implanted or activated <5 months prior to enrollment. Stimulation parameters that have been stable for <4 weeks, or Battery life of unit not anticipated to extend for duration of trial. 13. Subject is pregnant, may be pregnant, lactating or planning to be pregnant 14. Any suicidal ideation with intent, with or without a plan within 6 months before Visit 2 (i.e., answering "Yes" to question 4 or 5 in the Suicidal Ideation section of the age specific Columbia-Suicide Severuty Rating Scale (C-SSRS) in subjects aged 6 years and above who are able to be evaluated. 15. Any suicidal behavior within 2 years before Visit 2 (i.e., answering YES to any questions in the Suicidal behavior section of the age-specifc Columbia-Suicide Severity Rating Scale (C-SSRS) in subjects aged 6 and above who are able to be evaluated. 16. Evidence of significant active hepatic disease. Stable elevations of liver enzymes (alanine aminotransferase (ALT), and aspartate aminotransferase (AST)) due to concomitant medication(s) will be allowed if they are <3 x ULN 17. Subject with total bilirubin [TBL] >2 x ULN (except for Gilbert's syndrome). 18. Active viral hepatitis (B or C) as demonstrated by positive serology at the Screening visit (Visit 1) 19. History of positive antibody/antigen test for human immunodeficiency virus (HIV) 20. If taking Epidiolex, subject may not use other approved cannabidiol or over the counter cannabidiol products
Scheduled for epilepsy-related surgery, VNS insertion, or any other stimulators/surgery during the projected course of the study 22. Subject who has participated in any clinical study of an investigational product or device in the 30 days prior to the screening visit (Visit 1) 23. Concomitant use of medications known to be strong inducers of cytochrome UGT enzymes including, but not limited to: phenobarbital, phenytoin, carbamazepine, primidone, rifampin, troglitazone, St. John's Wort, efavirenz, nevirapine, glucocorticoids (other than topical usage), modafinil, pioglitazone, and rifabutin 24. Evidence of cardiac disease, including unstable angina, myocardial infarction, within the past 2 years, uncontrolled heart failure, major arrhythmias, congenital short QT syndrome 25. Subject with a short QTcF interval (<340 msec) or long QTcF interval (>460 msec) as confirmed by a repeated electrocardiogram (ECG) 26. Intermittent benzodiazepine rescue administered more than four times in the 28 days prior to Visit 1 (1 to 2 doses in a 24-hour period is considered as one rescue). 27. Previous exposure to carisbamate or sensitivity/allergy to components of the oral suspension.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Germany	Recruiting	28 Apr 2022	12
Greece	Not Recruiting	28 Apr 2022	12
Hungary	Recruiting	28 Apr 2022	4
Italy	Recruiting	28 Apr 2022	8
Poland	Recruiting	28 Apr 2022	24
Portugal	Recruiting	28 Apr 2022	23
Spain	Recruiting	28 Apr 2022	9